Vonoprazan hemifumarate and preparation method thereof

Abstract

The invention provides vonoprazan hemifumarate dihydrate which is a compound shown as a formula II: # imgabs0 #. The invention further provides a novel crystal form III of the vonoprazan hemifumarate dihydrate with excellent solubility, stability and non-hygroscopicity and a preparation method of the novel crystal form III of the vonoprazan hemifumarate dihydrate.

Description

[0001] This application claims the priority of a Chinese patent application titled "Vonoprazan Hemifumarate and Its Preparation Method" with the application number 202311625868.6 filed with the Chinese Patent Office on November 30, 2023, the entire content of which is incorporated herein by reference. Technical Field

[0002] The present invention relates to a new salt form of vonoprazan and its preparation method, and particularly to a new crystal form of vonoprazan hemifumarate and its preparation method. Background Art

[0003] Vonoprazan fumarate (English name: Vonoprazan fumarate, alias: TAK 438), chemical name: 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate, and its chemical formula is shown as formula (Ι):

[0004]

[0005] Vonoprazan fumarate is a potassium-competitive acid blocker that acts by competitively inhibiting potassium ions in hydrogen ion / potassium ion-ATPase. It is a reversible potassium ion antagonist and belongs to a new type of proton pump inhibitor, which is used to treat diseases such as duodenal ulcer, esophagitis, gastroesophageal reflux disease, eradication of Helicobacter pylori, peptic ulcer, and gastric ulcer.

[0006] Patent CN106604916B discloses that vonoprazan fumarate is dissolved in a solvent or solvent mixture (water / isopropanol, ethyl acetate / methanol, methanol, or water) to form a saturated or nearly saturated solution; the solution is cooled to about 5°C within 3 to 5 hours, stirred for 1 hour, filtered under reduced pressure, and the filter cake is dried at 50°C for 8 hours to obtain a 1:1 crystal form of vonoprazan fumarate.

[0007] Patent CN105315258A discloses that vonoprazan fumarate is obtained by mixing vonoprazan free base and fumaric acid in a solvent, and crystal forms A and B are obtained. The patent does not mention the results of the stability, solubility, and hygroscopicity of the compound of formula (I).

[0008] Patent CN107759568A discloses that the marketed dosage form of vonoprazan fumarate is tablets, which are not suitable for patients with dysphagia. Moreover, the poor water solubility of vonoprazan fumarate results in an oral bioavailability of only 10% for the product, restricting the acid-suppressing and treatment effects of diseases related to gastric acid and unable to well meet the clinical needs.

[0009] In Patent WO2010013823A1, the non-peptide drug active ingredient has a primary or secondary amino group and strong nucleophilicity. When the excipient in the pharmaceutical composition contains trace amounts of basic components, these basic components will act as basic catalysts and may cause problems brought about by the Michael addition reaction of α or β-unsaturated carbonyl compounds such as fumaric acid. Therefore, an acidic compound is added as a stabilizer in the commercialized originator brand pharmaceutical composition. The salt form may disproportionate and decompose into the free form in the preparation. Adding an acidic stabilizer also poses higher requirements for the quality control and stability of the preparation product.

[0010] Given the pharmaceutical value of this compound, its different solid forms and different crystal forms will affect the stability, homogeneity, bioavailability, efficacy and safety of the drug to varying degrees. Therefore, it is of great significance to develop a new solid form of vonoprazan with excellent properties to provide more and better choices for the subsequent development of the drug. Summary of the Invention

[0011] The first object of the present invention is to provide the hemifumarate dihydrate of the compound of formula I.

[0012] The second object of the present invention is to provide a new crystal form of the hemifumarate dihydrate of compound I with excellent solubility, stability and non-hygroscopicity and its preparation method.

[0013] The third object of the present invention is to provide a pharmaceutical composition containing the above-mentioned vonoprazan hemifumarate dihydrate or its crystal.

[0014] The fourth object of the present invention is to provide the use of the above-mentioned vonoprazan hemifumarate dihydrate or its crystal in the preparation of drugs for treating gastrointestinal ulcers, gastrointestinal inflammatory diseases or diseases related to gastric acid.

[0015] Therefore, in the first aspect, the present invention provides vonoprazan hemifumarate dihydrate, the compound of formula II as shown below.

[0016]

[0017] Vonoprazan hemifumarate dihydrate exists in crystalline form.

[0018] The second object of the present invention is to provide a new crystal form of vonoprazan hemifumarate dihydrate with excellent solubility, stability and non-hygroscopicity and its preparation method.

[0019] The present invention provides crystalline form III of vonoprazan hemifumarate dihydrate.

[0020] Preferably, the present invention provides crystalline form III of vonoprazan hemifumarate dihydrate, wherein the X-ray powder diffraction pattern of said crystalline form has characteristic peaks at 6.8±0.2°, 10.7±0.2° and 13.7±0.2°.

[0021] Preferably, the present invention provides crystalline form III of vonoprazan hemifumarate dihydrate, wherein the X-ray powder diffraction pattern of said crystalline form has characteristic peaks at 6.8±0.2°, 10.7±0.2°, 13.7±0.2°, 19.9±0.2°, 20.7±0.2° and 27.7±0.2°.

[0022] Preferably, the present invention provides crystalline form III of vonoprazan hemifumarate dihydrate, wherein the X-ray powder diffraction pattern of said crystalline form has characteristic peaks at 6.8±0.2°, 10.7±0.2°, 13.7±0.2°, 14.3±0.2°, 18.6±0.2°, 19.9±0.2°, 20.7±0.2° and 27.7±0.2°.

[0023] Preferably, the present invention provides crystalline form III of vonoprazan hemifumarate dihydrate, wherein the X-ray powder diffraction pattern of said crystalline form has characteristic peaks at 6.8±0.2°, 10.7±0.2°, 11.1±0.2°, 13.7±0.2°, 14.2±0.2°, 15.1±0.2°, 16.6±0.2°, 17.6±0.2°, 18.5±0.2°, 19.9±0.2°, 20.7±0.2°, 21.2±0.2°, 23.0±0.2°, 24.2±0.2°, 25.4±0.2°, 26.0±0.2°, 27.7±0.2°, 28.6±0.2°, 28.8±0.2°, 30.4±0.2°, 33.7±0.2° and 34.7±0.2°.

[0024] Preferably, the present invention provides crystalline form III of vonoprazan hemifumarate dihydrate, wherein the X-ray powder diffraction pattern of said crystalline form is substantially the same as Figure 5 the X-ray powder diffraction pattern shown.

[0025] The present invention provides a crystalline form III of the above-mentioned vonoprazan hemifumarate dihydrate, which is a single crystal, belonging to the triclinic system, space group P -1 , cell parameters: α = 104.911(1)°, β = 98.216(1)°, γ = 109.589(1)°, cell volume The number of asymmetric units Z = 2 in the unit cell, and the charge density is 1.413 g / cm 3 .

[0026] In a specific embodiment of the present invention, when the polymorph III provided by the present invention is subjected to differential scanning calorimetry (DSC) and heated from 25°C to 240°C at a heating rate of 10°C / min, the polymorph III has endothermic peaks at 109 ± 5°C and 152 ± 5°C.

[0027] Non-limitingly, in a specific embodiment of the present invention, the differential scanning calorimetry (DSC) pattern of the polymorph III of the present invention is substantially as shown in the appendix. Figure 6 as shown.

[0028] Non-limitingly, in a specific embodiment of the present invention, for the polymorph III provided by the present invention, when using a thermogravimetric analyzer (TGA) and heating from room temperature to 300°C at a heating rate of 10°C / min, the weight loss from room temperature to 120°C is about 9% or less, preferably about 8.8% or less, and more preferably about 7.7 - 8.7%. The polymorph III is a hydrate, with about two molecules of water per molecule of vonoprazan fumarate.

[0029] Furthermore, the thermogravimetric analysis (TGA) pattern of the polymorph III of the present invention is substantially as shown in the appendix. Figure 7 as shown.

[0030] In a specific embodiment of the present invention, the photograph (PLM) of the polymorph III of the present invention observed under a polarized light microscope is substantially as shown in Figure 8 as shown, wherein the polymorph III is rod-shaped crystals.

[0031] The present invention also provides a method for preparing the crystalline form III of vonoprazan fumarate dihydrate.

[0032] The present invention provides a first embodiment:

[0033] including the following steps:

[0034] Step 1: Vonoprazan fumarate reacts with an amine reagent in water or a mixed solvent of water and an organic solvent.

[0035] Step 2: Stir at a suitable temperature for a period of time, precipitate a solid, and dry to obtain the polymorph III.

[0036] The organic solvent in Step 1 is, for example, an alcohol solvent, an ether solvent, or a nitrile solvent.

[0037] The present invention provides a second embodiment:

[0038] Single crystal cultivation method: Take vonoprazan fumarate, add an appropriate amount of ammonia water with a mass fraction of 20 - 25%, stir until dissolved and clarified at 90°C, then cool naturally to precipitate, and stand and volatilize for 6 - 8 days to obtain transparent crystals, which are the polymorph III.

[0039] Further, Vorapaxar fumarate is not particularly limited and may be selected from Vorapaxar fumarate polymorph B, which is synthesized according to the preparation method described in patent document CN105315258A.

[0040] In certain embodiments, the amine reagent in the first embodiment is selected from, for example, ammonia water, ammonia solution, diethylamine, and triethylamine, and the ammonia solution is methanol, ethanol, isopropanol, dioxane, or tetrahydrofuran, with ammonia water being preferred.

[0041] Further, the mass fraction of the ammonia water is selected from 5% to 25%.

[0042] In certain embodiments, the molar ratio of Vorapaxar fumarate to ammonia water in step 1 of the first embodiment is 1:0.5 to 3, more preferably 1:0.5 to 2.

[0043] In certain embodiments, the mass-to-volume ratio (g:mL) of Vorapaxar fumarate to water in step 1 of the first embodiment is 1:10 to 50, more preferably 1:20 to 40.

[0044] In certain embodiments, the suitable temperature in step 2 of the first embodiment is selected from 25°C to 90°C, more preferably 40°C to 70°C; the reaction time is preferably 2 to 48 hours, more preferably 6 to 20 hours.

[0045] In certain embodiments, the drying temperature in step 2 of the first embodiment is more preferably vacuum drying at 20 to 40°C; the preferred drying time is 1 to 24 hours.

[0046] A third object of the present invention is to provide a pharmaceutical composition containing the above Vorapaxar fumarate dihydrate or its crystal.

[0047] According to another aspect of the present invention, there is also provided a pharmaceutical composition having an inhibitory effect on gastric acid secretion, which contains the semi-fumarate dihydrate of compound I (including its crystalline form III) defined herein as an active ingredient.

[0048] A pharmaceutical composition provided by the present invention contains a therapeutically and / or prophylactically effective amount of Vorapaxar fumarate dihydrate or its crystal, and at least one pharmaceutically acceptable excipient.

[0049] The pharmaceutical composition is selected from tablets, capsules, granules, powders, pills, powders, lozenges, syrups, suspensions suitable for oral administration, or aqueous or non-aqueous injection solutions or emulsions suitable for parenteral administration. The vonoprazan fumarate dihydrate of the present invention is more suitable for solid preparations using the wet granulation process or for making oral suspension dosage forms or injections because of its excellent thermodynamic stability, especially its stability to water and ethanol, and good solubility, and can remain stable during drug manufacturing and / or storage processes.

[0050] Further, the pharmaceutical composition is selected from tablets, capsules or suspensions suitable for oral administration.

[0051] Further, the tablets or capsules suitable for oral administration are prepared by the wet granulation process.

[0052] Further, the pharmaceutical composition of the vonoprazan fumarate dihydrate or its crystal provided by the present invention, wherein the excipient is any one or more selected from the following: mannitol, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polyvinylpyrrolidone, gum arabic powder, gelatin, low-substituted hydroxypropyl cellulose, crystalline cellulose, fumaric acid, succinic acid, acetic acid, tartaric acid, lactose, sucrose, starch, corn starch, titanium dioxide, light silica, magnesium stearate, talc or magnesium stearate, etc.

[0053] The fourth object of the present invention is to provide the use of the above-mentioned pharmaceutical composition of vonoprazan fumarate dihydrate or its crystal in the preparation of drugs for treating gastrointestinal ulcers, gastrointestinal inflammatory diseases or diseases related to gastric acid.

[0054] According to another aspect of the present invention, there is also provided a pharmaceutical composition having vonoprazan fumarate dihydrate or its crystal, which comprises the fumarate dihydrate or its crystal (including its crystalline form III) defined herein as an active ingredient, and the composition can be used for preparing drugs for duodenal ulcer, esophagitis, gastroesophageal reflux disease, eradicating Helicobacter pylori, peptic ulcer, and treating gastric ulcer, and it comprises the fumarate dihydrate (including its crystalline form III) defined herein.

[0055] The beneficial technical effects of the present invention are as follows:

[0056] The technical problem solved by the present invention is to provide a new crystal form different from the existing crystal forms. This crystal form has excellent stability and, compared with the existing crystal form B, has higher solubility, more uniform particle size distribution, smaller particle size, better fluidity, greater density, better compressibility, no solvent residue and is not prone to agglomeration, thus solving the problems existing in the prior art.

[0057] 1) Specifically, it has at least one of the following technical advantages: The present invention provides a novel vonoprazan fumarate sesquihydrate or its crystal.

[0058] 2) The crystal form III of vonoprazan fumarate sesquihydrate of the present invention has high purity, good stability, good crystallinity and good solubility.

[0059] Compared with the prior art crystal form B, the crystal form III provided by the present invention has higher solubility. The crystal form III of vonoprazan fumarate sesquihydrate of the present invention has an unexpected technical effect of improved solubility compared with the prior art crystal form vonoprazan fumarate Form B. The inventors of the present application believe that it is very difficult to double the solubility with the same salt radical. The crystal form III provided by the present invention has higher solubility, which is beneficial to improving the absorption of the drug in the human body and increasing the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the drug efficacy, thereby reducing the side effects of the drug and improving the safety of the drug.

[0060] 3) The preparation method of the crystal form III of vonoprazan fumarate sesquihydrate of the present invention is simple, the solvent is cheap and easily available, and it is suitable for large-scale industrial production. The crystal form III provided by the present invention has no solvent residue, effectively overcoming the disadvantages of low drug purity or high solvent residue, such as low drug stability, poor efficacy, high toxicity, etc., avoiding the conversion of crystals or the generation of impurities during the production and storage of drugs, and reducing the changes in drug bioavailability and toxic side effects.

[0061] 4) The crystal form III of vonoprazan fumarate sesquihydrate of the present invention can better combat problems such as uneven active ingredient content, reduced purity and increased impurities caused by environmental temperature, humidity and other factors during the processes of drug manufacturing and / or storage, etc., reducing the risk of reduced efficacy and safety risks brought thereby.

[0062] 5) The crystal form III of vonoprazan fumarate sesquihydrate of the present invention, compared with the prior art crystal form B, has a better crystal structure, good crystal morphology, uniform distribution, no agglomeration, smaller particle size, and a more uniform particle size distribution. The uniform particle size has no solvent wrapping residue, improves the product purity, ensures the content uniformity of the drug preparation, and reduces the variability of the in vitro dissolution rate. The smaller particle size helps the drug absorption, increases the solubility and bioavailability of the drug. In addition, it has advantages in at least one of the aspects of dosage, hygroscopicity, adhesiveness, fluidity, bioavailability, as well as processing performance, purification effect, preparation production, safety, etc., providing a new and better choice for the preparation of drug preparations containing vonoprazan fumarate sesquihydrate, and having very important significance for drug development.

[0063] 6) Compared with the existing polymorph B, the polymorph III provided by the present invention has better fluidity. The better fluidity can avoid clogging of production equipment, improve production efficiency; ensure the content uniformity of the preparation, reduce the weight difference, and improve product quality.

[0064] 7) The present invention has also screened the reaction temperature of the preparation methods of the first and second embodiments of polymorph III. If the temperature is too low, the reaction yield is low; if the temperature is too high, it will affect the accuracy of the reaction materials and the crystallization process. The present invention has screened a large number of amine reagents, and ammonia water is used as the preferred amine reagent, achieving unexpected technical effects. For example, if other amine reagents such as tetramethylethylenediamine are used, the target polymorph cannot be obtained at all, and mostly mixed crystals or non-dominant polymorphs are obtained; furthermore, if the ammonia water equivalent number is too high in the present invention, ammonium fumarate impurities will precipitate, inactive substance products will precipitate, and the product is a mixed crystal or only ammonium fumarate is obtained.

[0065] 8) The polymorph III raw material drug provided by the present invention has good stability. When the polymorph III raw material drug is placed under the conditions of 25°C / 60% RH, the polymorph has not changed for at least 3 months, and the purity remains basically unchanged during storage. At the same time, when the polymorph III raw material drug is placed under the conditions of 40°C / 75% RH for at least 6 months, the polymorph has not changed, and the purity remains basically unchanged during storage. Polymorph III has good photo-stability. When applied to the preparation, its good light stability does not require the additional addition of organic acids in the preparation formula, saving costs and reducing the clinical application toxicity and side effects of excipients. The good physical and chemical stability of the raw material drug polymorph can also ensure that the drug does not undergo polymorphic transformation and basically no impurities are generated during production and storage. Polymorph III has good physical and chemical stability, ensuring the consistency and controllability of the quality of the raw material drug and the preparation, reducing the drug quality changes, bioavailability changes, and toxicity and side effects caused by polymorphic changes or impurity generation. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1 is the X-ray powder diffraction (XPRD) spectrum of polymorph B of the present invention;

[0067] Figure 2 is the differential scanning calorimetry (DSC) spectrum of polymorph B of the present invention;

[0068] Figure 3 is the thermogravimetric analysis (TGA) spectrum of polymorph B of the present invention;

[0069] Figure 4 is the polarized light microscopy (PLM) spectrum of polymorph B of the present invention;

[0070] Figure 5 is the X-ray powder diffraction (XPRD) spectrum of polymorph III of the present invention;

[0071] Figure 6 It is the differential scanning calorimetry (DSC) spectrum of polymorph III of the present invention;

[0072] Figure 7 It is the thermogravimetric analysis (TGA) spectrum of polymorph III of the present invention;

[0073] Figure 8 It is the polarized light microscopy (PLM) spectrum of polymorph III of the present invention;

[0074] Figure 9 It is the 1H NMR spectrum of polymorph III of the present invention;

[0075] Figure 10 It is the crystal cell packing diagram of the single crystal obtained in Example 2 of the present invention;

[0076] Figure 11 It is the simulated X-ray powder diffraction (XPRD) pattern of the single crystal obtained in Example 2 of the invention;

[0077] Figure 12 It is the superposition diagram of the X-ray powder diffraction (XPRD) pattern of polymorph III of the present invention and the single crystal data obtained in Example 2;

[0078] Figure 13 It is the dynamic vapor sorption (DVS) spectrum of polymorph III of the present invention;

[0079] Figure 14 It is the XRPD superposition diagram of the sample of polymorph III of the present invention before and after DVS. Detailed implementation manners

[0080] The present invention will be further described below in conjunction with specific embodiments. It should be understood that the following detailed description of the technical solutions of the present invention with examples will help to further understand the advantages and effects of the technical solutions of the present invention. The embodiments do not limit the protection scope of the present invention.

[0081] For the experimental methods without specific conditions indicated in the following embodiments, they are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0082] Unless otherwise specified, the raw materials or reagents used in the embodiments are all commercially available.

[0083] The XPRD pattern was collected on a Bruker D8 Advance diffractometer, and the method parameters of the X-ray powder diffraction are as follows:

[0084] X-ray reflection parameter: Cu, Kα

[0085] Tube voltage: 40 kilovolts (kV)

[0086] Tube current: 40 milliamperes (mA)

[0087] Slits: Primary optical path Soller slit 2.5°, secondary optical path Soller slit 2.5°

[0088] Scanning mode: Continuous scanning

[0089] Step angle: 0.02°, sampling time: 0.1 s / step;

[0090] Scanning range: From 3.0 to 40.0 degrees

[0091] The TGA spectrum was collected on a TA Instruments Discovery TGA 55 instrument. The method parameters of the thermogravimetric analysis are as follows:

[0092] Scanning rate: 10 °C / minute

[0093] Protective gas: Nitrogen

[0094] The DSC spectrum was collected on a TA Instruments Discovery DSC250 instrument

[0095] Test conditions: Heating from 25 °C to 220 °C at a rate of 10 °C / minute;

[0096] Detection environmental conditions: Room temperature: 21 °C.

[0097] The polarized light microscope (PLM) images were taken from an XP-500E polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). A small amount of powder sample was placed on a glass slide, a small amount of mineral oil was added to better disperse the powder sample, a coverslip was covered, and then the sample was placed on the stage of the XP-500E polarized light microscope. An appropriate magnification was selected to observe the morphology of the sample and take pictures.

[0098] Example 1

[0099] Preparation of polymorph B

[0100] Refer to the preparation method in Example 2 of Patent Document CN105315258A to synthesize voronolazine fumarate polymorph B. Specifically: Add 46.1 g (0.1 mol) of voronolazine fumarate polymorph A to a 2000 ml single-necked flask, and add 922 ml of a methanol and water (ratio 1:1) mixed solution. Dissolve in a water bath at 50 - 60 °C, stir and cool to room temperature, filter by suction after stirring for 1 hour, and vacuum dry the filter cake at 50 °C to constant weight to obtain 36.8 g of voronolazine fumarate polymorph B, with a molar yield of 79.8%. The X-ray powder diffraction and DSC spectra of the obtained voronolazine fumarate polymorph B sample are respectively as Figure 1 、 Figure 2As shown, it is basically the same as the X-ray powder diffraction and DSC spectra of the compound B crystal form provided by CN105315258A. The TGA and the photos (PLM) observed under a polarized light microscope of this B crystal form are respectively Figure 3 and Figure 4 as shown.

[0101] Example 2

[0102] Single crystal cultivation method: Take 30 mg of crystal form B, add 1.35 mL of ammonia water with a mass fraction of 20%, stir and dissolve it clearly at 90 °C, then cool it naturally to precipitate, and let it stand and volatilize for about one week to obtain transparent crystals, which are crystal form III.

[0103] The crystal cell packing diagram of voronrazan hemifumarate dihydrate crystal form III is as Figure 10 shown, and the single crystal simulated XPRD spectrum is as Figure 11 shown.

[0104] The crystallographic parameters of the single crystal of voronrazan hemifumarate dihydrate are shown in Table 1 below:

[0105] Table 1 Crystallographic parameters of the single crystal of voronrazan hemifumarate dihydrate

[0106]

[0107]

[0108] Example 3

[0109] Take 300 mg of crystal form B, add 0.6 mL of ammonia water solution with a mass fraction of 9%, then add 10 ml of purified water, stir and dissolve it clearly at 60 °C, then cool it to room temperature. After stirring at room temperature for about 20 min, white solid precipitates. Stir overnight, centrifuge and filter. The filter cake is dried in vacuum at 25 °C for 8 h to obtain 189 mg of crystalline powder, with a yield of 63% and a purity of 99.07%, which is determined to be FormIII.

[0110] The XRPD spectrum is as Figure 5 shown. The X-ray powder diffraction pattern of the crystal form III has specific peaks at 2θ of 6.8±0.2°, 10.7±0.2°, 13.8±0.2°, 14.3±0.2°, 18.6±0.2°, 20.7±0.2° and 27.8±0.2°, and has one or more of the following characteristic peaks: 15.1±0.2°, 16.6±0.2°, 17.6±0.2°, 21.3±0.2°, 23.0±0.2°, 24.2±0.2°, 25.4±0.2°, 26.1±0.2°, 28.6±0.2°, 28.8±0.2° and 30.4±0.2°.

[0111] The DSC spectrum of the crystalline form III is as shown in Figure 6 , and the TGA spectrum is as shown in Figure 7 . The results show that the TGA data of the crystalline form III show that there is a weight loss of about 7.9% during heating of this crystalline form between 0 and 120 °C, and there are two endothermic peaks between room temperature and 220 °C in DSC. 1 The 1H-NMR nuclear magnetic resonance spectrum is as shown in Figure 9 . The 1H-NMR spectrum shows 0.5 molecule of fumaric acid and one molecule of vonoprazan, indicating that this crystalline form is vonoprazan fumarate hemihydrate.

[0112] Weigh about 10 mg of the crystalline form III of the present invention, and use a dynamic vapor sorption (DVS) instrument to test its hygroscopicity. It is cycled once under relative humidities of 60% - 95% - 0% - 95%, and the mass change at each humidity is recorded, and XRPD tests are carried out before and after the DVS test. The DVS diagram of the crystalline form III is as shown in Figure 13 , and the XRPD before and after the hygroscopicity determination is as shown in Figure 14 . Moreover, the PXRD pattern shows that the crystalline form does not change before and after the DVS test. The crystalline form III has a weight gain of less than 0.2% at 50% RH - 80% RH, belonging to non-hygroscopic or almost non-hygroscopic, meeting the requirements for hygroscopicity of pharmaceutical raw materials.

[0113] Example 4

[0114] Take 50 mg of crystalline form B, add 0.1 mL of ammonia water solution with a mass fraction of 5%, then add 2 mL of purified water, stir at 60 °C for 30 min until it becomes clear, then cool to room temperature. After stirring at room temperature for about 20 min, white solids precipitate out. Stir overnight, centrifuge and filter. The filter cake is dried in vacuo at 25 °C for 8 h to obtain 31 mg of crystalline powder, with a yield of 62% and a purity of 99.21%, which is determined to be crystalline form III.

[0115] The X-ray powder diffraction pattern measured using Cu-Kα radiation of the prepared crystal is the same as that in Example 3.

[0116] Example 5

[0117] Weigh about 10 mg each of crystalline form B and crystalline form III, place them on a glass slide respectively, add a little vacuum silicone oil to disperse the samples, then cover with a cover glass, and observe under a polarized light microscope. The polarized light microscope observation photos (PLM) of crystalline form B and crystalline form III are as shown in Figure 4 and Figure 8 respectively. It can be seen from the figure that the crystal morphology of crystalline form B is blocky, while the crystal morphology of the crystalline form III of the present invention is rod-shaped, and the crystalline form III of the present invention has a better dispersion degree than crystalline form B, and the crystalline form III of the present invention has a better crystal habit than crystalline form B.

[0118] Example 6

[0119] Stability experiment

[0120] The crystalline form III samples obtained in any of the above embodiments were placed open to the air for 7 days under different temperature and humidity environments, and the samples were taken to measure XRPD and HPLC. The results are shown in Table 2 below.

[0121] Table 2. Stability study

[0122]

[0123] From the data in Table 2 above, it can be seen that the crystalline form III of the present invention is stable in crystalline form and the chemical purity is not reduced at 25°C / 60% RH and 40°C / 75% RH, showing good chemical stability.

[0124] Example 7

[0125] The crystalline form III with a purity of 100% was prepared by referring to the method of Example 3 and the crystalline form B with a purity of 99.98% was obtained by referring to the method of Example 1. The crystalline form III and the crystalline form B were placed open to the air for 6 months under different temperature and humidity environments, and the samples were taken to measure XRPD and HPLC. The results are shown in Table 3 below.

[0126] Table 3. Stability study

[0127]

[0128] From the data in Table 3 above, it can be seen that the crystalline form III of the present invention is stable in crystalline form and the chemical purity is higher than 99.96% after being placed at 25°C / 60% RH and 40°C / 75% RH for 3 months and 6 months, showing good chemical stability.

[0129] Example 8

[0130] Solubility experiment

[0131] For the crystalline form B and crystalline form III samples obtained in the above embodiments, a certain amount of the samples was weighed and placed in different solvent systems. After maintaining at 37°C and stirring for a certain time, 0.2 ml of the samples were taken and diluted 4 times, then filtered through a 0.45 μm microporous filter membrane. The drug content of the continued filtrate was measured to obtain the solubility in water (mg / ml). The results are shown in Table 4:

[0132] Table 4. Solubility data of the crystalline forms of the present invention and the reference substance in different solvent systems:

[0133]

[0134] As can be seen from the data in Table 4 above, the solubility of polymorph III of the present invention in 1.2 hydrochloric acid solution is about 2 times higher than that of the reference polymorph B, and it is better than Form B in other buffer solutions and pure water, showing good solubility.

[0135] Example 9

[0136] Photostability experiment

[0137] Weigh a certain mass of Form III, the polymorph III sample obtained from the above example, and place it in a strong light irradiation test chamber (test conditions: Illuminance is 5000±500Lux, 80~100uW / cm 2 , instrument model: SHH-300GD-2F), and take samples for HPLC content testing at 2h, 6h, 24h, 5D, 10D and 30D. The experimental results are shown in Table 5:

[0138] Table 5: Photostability data of the polymorph of the present invention and the reference

[0139]

[0140] As can be seen from the above table, the purity of Form III has not decreased and it has photostability.

[0141] The above description of the embodiments is to enable those of ordinary skill in the art to understand and use the invention. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative efforts. Therefore, the present invention is not limited to the above embodiments, and the improvements and modifications made by those skilled in the art without departing from the scope of the present invention should be within the protection scope of the present invention.

Claims

1. A hemifumarate vonoprazan dihydrate, as shown in the following formula II:

2. According to claim 1, vonoprazan hemifumarate dihydrate is in crystalline form III, characterized in that The X-ray powder diffraction pattern of the crystalline form has characteristic peaks at 6.8±0.2°, 10.7±0.2° and 13.7±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form has specific peaks at 6.8±0.2°, 10.7±0.2° and 13.7±0.2° and has one or more of the following characteristic peaks: 11.1±0.2°, 14.2±0.2°, 15.1±0.2°, 16.6 ±0.2°, 17.6±0.2°, 18.5±0.2°, 19.9±0.2°, 20.7±0.2°, 21.2±0.2°, 23.0±0.2°, 24.2±0.2°, 25.4±0.2°, 26.0±0.2°, 27.7±0.2°, 28.6±0.2°, 28.8±0.2°, 30.4±0.2°, 33.7±0.2° and 34.7±0.2°.

3. According to claim 2, vonoprazan hemifumarate dihydrate is in crystalline form III, characterized in that The X-ray powder diffraction pattern of the crystalline form III is substantially the same as the X-ray powder diffraction pattern shown in FIG. 5 .

4. The vonoprazan hemifumarate dihydrate according to claim 2, which is in crystalline form III, characterized in that The preparation method satisfies one or more of the following conditions: 1) The differential scanning calorimetry (DSC) spectrum of the crystalline form III is substantially the same as the DSC spectrum shown in FIG6 , and DSC has endothermic peaks at 109±5° C. and 152±5° C.; 2) The thermogravimetric analysis (TGA) spectrum of the crystalline form III is substantially the same as the TGA spectrum shown in FIG. 7 , and the TGA weight loss from room temperature to 120° C. is about 9% or less, preferably about 8.8% or less, and more preferably about 7.7-8.7%.

5. Vonoprazan hemifumarate dihydrate according to claim 2, which is in crystalline form III, characterized in that Polarized light microscopy (PLM) of the crystalline form III showed that the crystals were rod-shaped, which was substantially the same as the PLM pattern shown in FIG8 .

6. Vonoprazan hemifumarate dihydrate according to claim 2, which is in crystalline form III, characterized in that The crystalline form III belongs to the triclinic system, P -1 Space group, unit cell parameters: α=104.911(1)°, β=98.216(1)°, γ=109.589(1)°.

7. A method for preparing vonoprazan hemifumarate dihydrate and its crystalline form III as described in any one of claims 1 to 6, comprising the following steps: Step 1: reacting vonoprazan fumarate with an amine reagent in water or a mixed solvent of water and an organic solvent; Step 2: Stir for a period of time at a suitable temperature to precipitate solid and dry to obtain Form III.

8. The preparation method according to claim 7, characterized in that: The preparation method satisfies one or more of the following conditions: 1) The amine reagent in step 1 is selected from ammonia water, ammonia gas solution, diethylamine, triethylamine, wherein the ammonia gas solution is methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, preferably ammonia water; 2) the organic solvent described in step 1, such as an alcohol solvent, an ether solvent, or a nitrile solvent; 3) When the amine reagent in step 1 is aqueous ammonia, the molar ratio of vonoprazan fumarate to aqueous ammonia is 1:0.5-3, preferably 1:0.5-2; 4) The mass fraction of the ammonia water in step 1 is selected from 5% to 25%; 5) The mass volume ratio (g:mL) of vonoprazan fumarate to water in step 1 is 1:10 to 50, preferably 1:20 to 40; 6) The suitable temperature in step 2 is selected from 25°C to 90°C, more preferably 40°C to 70°C; 7) The reaction time of step 2 is preferably 2 to 48 hours, more preferably 6 to 20 hours; 8) The drying temperature of step 2 is preferably 20 to 40° C. in vacuum drying; the drying time is preferably 1 to 24 hours.

9. A pharmaceutical composition comprising vonoprazan hemifumarate dihydrate or crystalline form III according to any one of claims 1 to 6 and at least one pharmaceutically acceptable carrier.

10. Use of the vonoprazan hemifumarate dihydrate or crystals of crystalline form III as claimed in any one of claims 1 to 6 in the preparation of drugs for treating duodenal ulcer, esophagitis, gastroesophageal reflux disease, eradication of Helicobacter pylori, peptic ulcer, and gastric ulcer.

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